Certain aryl fused imidazopyrimidines; a new class of GABA brain receptor ligands

ABSTRACT

Disclosed is a method for treating a subject non-human animal or domestic pet exhibiting symptoms of anxiety with a compound of the formula: ##STR1## wherein X is oxygen or sulfur; 
     W is (un)substituted phenyl, thienyl or pyridyl; and ##STR2## represents (un)substituted aryl or heteroaryl as defined in the specification.

This application is a continuation-in-part of U.S. application Ser. No.08/845,326, filed Apr. 25, 1997, now U.S. Pat. No. 5,817,813, which is acontinuation of U.S. application Ser. No. 08/553,357, filed Mar. 14,1996, now U.S. Pat. No. 5,625,063, which is a continuation ofInternational Application PCT/US93/04095, filed May 6, 1993, which is acontinuation-in-part of U.S. application Ser. No. 07/810,684, filed Dec.19, 1991, now U.S. Pat. No. 5,212,310.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to certain aryl fused imidazopyrimidines whichselectively bind to GABAa receptors. This invention also relates topharmaceutical compositions comprising such compounds. It furtherrelates to the use of such compounds in treating anxiety, sleep andseizure disorders, and overdoses of benzodiazepine-type drugs, andenhancing alertness. The interaction of aryl fused imidazopyrimidines ofthe invention with a GABA binding site, the benzodiazepines (BDZ)receptor, is described. This interaction results in the pharmacologicalactivities of these compounds.

2. Description of the Related Art

γ-Aminobutyric acid (GABA) is regarded as one of the major inhibitoryamino acid transmitters in the mammalian brain. Over 30 years haveelapsed since its presence in the brain was demonstrated (Roberts &Frankel,. J. Biol. Chem 187: 55-63, 1950; Udenfriend, J. Biol. Chem.187: 65-69, 1950). Since that time, an enormous amount of effort hasbeen devoted to implicating GABA in the etiology of seizure disorders,sleep, anxiety and cognition (Tallman and Gallager, Ann. Rev.Neuroscience 8: 21-44, 1985). Widely, although unequally, distributedthrough the mammalian brain, GABA is said to be a transmitter atapproximately 30% of the synapses in the brain. In most regions of thebrain, GABA is associated with local inhibitory neurons and only in tworegions is GABA associated with longer projections. GABA mediates manyof its actions through a complex of proteins localized both on cellbodies and nerve endings; these are called GABAa receptors. Postsynapticresponses to GABA are mediated through alterations in chlorideconductance that generally, although not invariably, lead tohyperpolarization of the cell. Recent investigations have indicated thatthe complex of proteins associated with postsynaptic GABA responses is amajor site of action for a number of structurally unrelated compoundscapable of modifying postsynaptic responses to GABA. Depending on themode of interaction, these compounds are capable of producing a spectrumof activities (either sedative, anxiolytic, and anticonvulsant, orwakefulness, seizures, and anxiety).

1,4-Benzodiazepines continue to be among the most widely used drugs inthe world. Principal among the benzodiazepines marketed arechlordiazepoxide, diazepam, flurazepam, and triazolam. These compoundsare widely used as anxiolytics, sedative-hypnotics, muscle relaxants,and anticonvulsants. A number of these compounds are extremely potentdrugs; such potency indicates a site of action with a high affinity andspecificity for individual receptors. Early electrophysiological studiesindicated that a major action of benzodiazepines was enhancement ofGABAergic inhibition. The benzodiazepines were capable of enhancingpresynaptic inhibition of a monosynaptic ventral root reflex, aGABA-mediated event (Schmidt et al., 1967, Arch. Exp. Path. Pharmakol.258: 69-82). All subsequent electrophysiological studies (reviewed inTallman et al. 1980, Science 207:274-81, Haefley et al., 1981, Handb.Exptl. Pharmacol. 33: 95-102) have generally confirmed this finding, andby the mid-1970s, there was a general consensus amongelectrophysiologists that the benzodiazepines could enhance the actionsof GABA.

With the discovery of the "receptor" for the benzodiazepines and thesubsequent definition of the nature of the interaction between GABA andthe benzodiazepines, it appears that the behaviorally importantinteractions of the benzodiazepines with different neurotransmittersystems are due in a large pan to the enhanced ability of GABA itself tomodify these systems. Each modified system, in turn, may be associatedwith the expression of a behavior.

Studies on the mechanistic nature of these interactions depended on thedemonstration of a high-affinity benzodiazepine binding site (receptor).Such a receptor is present in the CNS of all vertebratesphylogenetically newer than the boney fishes (Squires & Braestrup 1977,Nature 166: 732-34, Mohler & Okada, 1977, Science 198: 854-51, Mohler &Okada, 1977, Br. J. Psychiatry 133: 261-68). By using tritiateddiazepam, and a variety of other compounds, it has been demonstratedthat these benzodiazepine binding sites fulfill many of the criteria ofpharmacological receptors; binding to these sites in vitro is rapid,reversible, stereospecific, and saturable. More importantly, highlysignificant correlations have been shown between the ability ofbenzodiazepines to displace diazepam from its binding site and activityin a number of animal behavioral tests predictive of benzodiazepinepotency (Braestrup & Squires 1978, Br. J. Psychiatry 133: 249-60, Mohler& Okada. 1977, Science 198: 854-51, Mohler & Okada, 1977, Br. J.Psychiatry 133: 261-68). The average therapeutic doses of these drugs inman also correlate with receptor potency (Tallman et al. 1980, Science207: 274-281).

In 1978, it became clear that GABA and related analogs could interact atthe low affinity (1 mM) GABA binding site to enhance the binding ofbenzodiazepines to the clonazepam-sensitive site (Tallman et al. 1978,Nature, 274: 383-85). This enhancement was caused by an increase in theaffinity of the benzodiazepine binding site due to occupancy of the GABAsite. The data were interpreted to mean that both GABA andbenzodiazepine sites were allosterically linked in the membrane as panof a complex of proteins. For a number of GABA analogs, the ability toenhance diazepam binding by 50% of maximum and the ability to inhibitthe binding of GABA to brain membranes by 50% could be directlycorrelated. Enhancement of benzodiazepine binding by GABA agonists isblocked by the GABA receptor antagonist (+) bicuculline; thestereoisomer (-) bicuculline is much less active (Tallman et al., 1978,Nature, 24: 383-85).

Soon after the discovery of high affinity binding sites for thebenzodiazepines, it was discovered that a triazolopyridazine couldinteract with benzodiazepine receptors in a number of regions of thebrain in a manner consistent with receptor heterogeneity or negativecooperativity. In these studies. Hill coefficients significantly lessthan one were observed in a number of brain regions, including cortex,hippocampus, and striatum. In cerebellum, triazolopyridazine interactedwith benzodiazepine sites with a Hill coefficient of 1 (Squires et al.,1979, Pharma. Biochem. Behav. 10: 825-30, Klepner et al. 1979,Pharmacol. Biochem. Behav. 11: 457-62). Thus, multiple benzodiazepinereceptors were predicted in the cortex, hippocampus, striatum, but notin the cerebellum.

Based on these studies, extensive receptor autoradiographic localizationstudies were carried out at a light microscopic level. Although receptorheterogeneity has been demonstrated (Young & Kuhar 1980, J. Pharmacol.Exp. Ther. 212: 337-46, Young et al., 1981 J. Pharmacol Exp. ther 216:425-430. Niehoff et al. 1982, J. Pharmacol. Exp. Ther. 221: 670-75), nosimple correlation between localization of receptor subtypes and thebehaviors associated with the region has emerged from the early studies.In addition, in the cerebellum, where one receptor was predicted frombinding studies, autoradiography revealed heterogeneity of receptors(Niehoff et al., 1982, J. Pharmacol. Exp. Ther. 221: 670-75).

A physical basis for the differences in drug specificity for the twoapparent subtypes of benzodiazepine sites has been demonstrated bySieghart & Karobath, 1980, Nature 286: 285-87. Using gel electrophoresisin the presence of sodium dodecyl sulfate, the presence of severalmolecular weight receptors for the benzodiazepines has been reported.The receptors were identified by the covalent incorporation ofradioactive flunitrazepam, a benzodiazepine which can covalently labelall receptor types. The major labeled bands have molecular weights of50,000 to 53,000, 55,000, and 57,000 and the triazolopyridazines inhibitlabeling of the slightly higher molecular weight forms (53,000, 55,000,57,000) (Seighart et al. 1983, Eur. J. Pharmacol. 88: 291-99).

At that time, the possibility was raised that the multiple forms of thereceptor represent "isoreceptors" or multiple allelic forms of thereceptor (Tallman & Gallager 1985, Ann. Rev. Neurosci. 8, 21-44).Although common for enzymes, genetically distinct forms of receptorshave not generally been described. As we begin to study receptors usingspecific radioactive probes and electrophoretic techniques, it is almostcertain that isoreceptors will emerge as important in investigations ofthe etiology of psychiatric disorders in people.

The GABAa receptor subunits have been cloned from bovine and human cDNAlibraries (Schoenfield et al., 1988; Duman et al., 1989). A number ofdistinct cDNAs were identified as subunits of the GABAa receptor complexby cloning and expression. These are categorized into ∝, β, γ, δ, ε andprovide a molecular basis for the GABAa receptor heterogeneity anddistinctive regional pharmacology (Shivvers et al., 1980; Levitan etal., 1989). The g subunit appears to enable drugs like benzodiazepinesto modify the GABA responses (Pritchett et al., 1989). The presence oflow Hill coefficients in the binding of ligands to the GABAa receptorindicates unique profiles of subtype specific pharmacological action.

Drugs that interact at the GABAa receptor can possess a spectrum ofpharmacological activities depending on their abilities to modify theactions of GABA. For example, the beta-carbolines were first isolatedbased upon their ability to inhibit competitively the binding ofdiazepam to its binding site (Nielsen et al., 1979, Life Sci. 25:679-86). The receptor binding assay is not totally predictive about thebiological activity of such compounds: agonists, partial agonists,inverse agonists, and antagonists can inhibit binding. When thebeta-carboline structure was determined, it was possible to synthesize anumber of analogs and test these compounds behaviorally. It wasimmediately realized that the beta-carbolines could antagonize theactions of diazepam behaviorally (Tenen & Hirsch. 1980, Nature 288:609-10). In addition to this antagonism, beta-carbolines possessintrinsic activity of their own opposite to that of the benzodiazepines;they become known as inverse agonists.

In addition, a number of other specific antagonists of thebenzodiazepine receptor were developed based on their ability to inhibitthe binding of benzodiazepines. The best studied of these compounds isan imidazodiazepine (Hunkeler et al., 1981, Nature 290: 514-516). Thiscompound is a high affinity competitive inhibitor of benzodiazepine andbeta-carboline binding and is capable of blocking the pharmacologicalactions of both these classes of compounds. By itself, it possesseslittle intrinsic pharmacological activity in animals and humans(Hunkeler et al., 1981, Nature 290: 514-16; Darragh et al., 1983, Eur.J. Clin. Pharmacol. 14: 569-70). When a radiolabeled form of thiscompound was studied (Mohler & Richards. 1981, Nature 294: 763-65), itwas demonstrated that this compound would interact with the same numberof sites as the benzodiazepines and beta-carbolines, and that theinteractions of these compounds were purely competitive. This compoundis the ligand of choice for binding to GABAa receptors because it doesnot possess receptor subtype specificity and measures each state of thereceptor.

The study of the interactions of a wide variety of compounds similar tothe above has led to the categorizing of these compounds. Presently,those compounds possessing activity similar to the benzodiazepines arecalled agonists. Compounds possessing activity opposite tobenzodiazepines are called inverse agonists, and the compounds blockingboth types of activity have been termed antagonists. This categorizationhas been developed to emphasize the fact that a wide variety ofcompounds can produce a spectrum of pharmacological effects, to indicatethat compounds can interact at the same receptor to produce oppositeeffects, and to indicate that beta-carbolines and antagonists withintrinsic anxiogenic effects are not synonymous.

A biochemical test for the pharmacological and behavioral properties ofcompounds that interact with the benzodiazepine receptor continues toemphasize the interaction with the GABAergic system. In contrast to thebenzodiazepines, which show an increase in their affinity due to GABA(Tallman et al., 1978, Nature 274: 383-85, Tallman et al., 1980, Science207: 274-81), compounds with antagonist properties show little GABAshift (i.e., change in receptor affinity due to GABA) (Mohler & Richards1981, Nature 294: 763-65), and the inverse agonists actually show adecrease in affinity due to GABA (Braestirup & Nielson 1981, Nature 294:472-474). Thus, the GABA shift predicts generally the expectedbehavioral properties of the compounds.

Various compounds have been prepared as benzodiazepine agonists andantagonists. For example. U.S. Pat. Nos. 4,312,870 and 4,713,383, andEuropean Patent Application EP 181,282 disclose assorted compoundsuseful in treating anxiety or depression. U.S. Pat. No. 4,713,383teaches compounds of the formula: ##STR3## wherein R₁ =(un)substitutedPh, (dihydro)furanyl, tetrahydrofuranyl, (dihydro)thienyltetrahydrothienyl, pyranyl, ribofuranosyl, all C-attached; R₂ =H,alklyl; X=O, S, R₃ N; R₃ =H, alkenyl, alkynyl, C₃₋₂₀ cycloalkyl,(un)substituted alkyl, aryl, aralkyl, where aryl is Ph, pyridinyl,thienyl, furanyl; ring A may be substituted by alkyl, alkoxy, halo,amino, alkylthio, etc.

European Patent Application EP 181,282 discloses compounds of theformula: ##STR4## wherein R₁ =(substituted) Ph or heterocycle; R₂ =H,alkyl, alkenyl, hydroxyalkyl, aralkyl, aralkenyl, aryl. R₃ =H, alkyl,alkoxy. HO, halo, F₃ C, O₃ N, H₂ N, alkylthio, alkylsulfinyl,alkylsulfonyl, aralkoxy; X=O, S, NR₄ ; and R₄ =H, alkyl, aralkyl,cycloalkyl, alkenyl, alkynyl, aryl, (substituted) aminoaklyl,hydroxyalkyl.

U.S. Pat. No. 4,312,870 teaches compounds of formulas: ##STR5## where Phis 1,2-phenylene, unsubstituted or substituted by up to 3 identical ordifferent members selected from lower alkyl, lower alkoxy, loweralkylthio, hydroxy, halogeno, trifluoromethyl, nitro, amino, mono- ordi-lower alkylamino, cyano, carbamoyl and carboxy; R is unsubstituted orsubstituted phenyl as defined by H--Ph, pyridyl, lower alkylpyridyl, orhalogenopyridyl; R₁ is hydrogen, lower alkyl or lower (hydroxy,dialkylamino or H--Ph)-alkyl; and R₂ is hydrogen or lower alkyl alkyl;their 3-hydroxytautomers; lower alkanoyl, carbamoyl, mono- or di-loweralkylcarbamoyl derivatives of said (hydroxy or amino)-(phenyl orphenylene) compounds; and ##STR6## where R" is hydrogen, alkyl or alkoxywith up to 4 carbon atoms each, hydroxy, fluoro, chloro, bromo, ortrifluoromethyl; and R' is hydrogen, o- or m-fluoro; or it is p-fluorowhen R" is chloro.

The compounds of the present invention differ from these compounds.These compounds are not imidazoquinoxalines and lack the various ringsubstituents of the compounds of the present invention.

SUMMARY OF THE INVENTION

This invention provides novel compounds of Formula I which interact witha GABAa binding site, the benzodiazepine receptor.

The invention provides pharmaceutical compositions comprising compoundsof Formula I. The invention also provides compounds useful in enhancingalertness, treatment of seizure, anxiety, and sleep disorders, andtreatment of benzodiazepine overdoses. Accordingly, a broad embodimentof the invention is directed to compounds of Formula I: ##STR7## or thepharmaceutically acceptable non-toxic salts thereof wherein: X is oxygenor sulfur;

W is

phenyl, thienyl, or pyridyl, or

phenyl, thienyl, or pyridyl, each of which may be mono or disubstitutedwith halogen, hydroxy, straight or branched chain lower alkyl having 1-6carbon atoms, amino, mono or dialkylamino where each alkyl is straightor branched chain lower alkyl having 1-6 carbon atoms, or straight orbranched chain lower alkoxy having 1-6 carbon atoms; ##STR8## wherein: Arepresents nitrogen or C--R₁ ;

B represents nitrogen or C--R₂ with the proviso that not both A and Bare nitrogen;

C represents nitrogen or C--R₁ ;

D represents nitrogen or C--R₂ with the proviso that not both C and Dare nitrogen;

E represents oxygen, sulfur or N--R₅ ;

R₁ and R₄ are the same or different and represent

hydrogen, halogen, straight or branched chain lower alkyl having 1-6carbon atoms, or straight or branched chain lower alkoxy having 1-6carbon atoms;

R₂ is

hydrogen, halogen, hydroxy, amino, 1-indanyl, 4-(thia)deoxachromanyl,1-(1,2,3,4-tetrahydronaphthyl);

1-indanyl, 4-(thia)deoxachromanyl, 1-(1,2,3,4-tetrahydronaphthyl), eachof which is monosubstituted with halogen, straight or branched chainlower alkyl having 1-6, carbon atoms, or straight or branched chainlower alkoxy having 1-6 carbon atoms;

OR₅, COR₅, CO₂ R₅, OCOR₅, or R₅, where R₅ is hydrogen, phenyl, pyridyl,straight or branched chain lower alkyl having 1-6 carbon atoms, orphenylalkyl or pyridylalkyl where each alkyl is straight or branchedchain lower alkyl having 1-6 carbon atoms;

--CONR₆ R₇ or --(CH₂)_(n) NR₆ R₇ where

n is 0, 1, or 2;

R₆ is hydrogen, straight or branched chain lower alkyl having 1-6 carbonatoms; and

R₇ is hydrogen, phenyl, pyridyl, straight or branched chain lower alkylhaving 1-6 carbon atoms, or phenylalkyl or pyridylalkyl where each alkylis straight or branched chain lower alkyl having 1-6 carbon atoms, or

NR₆ R₇ forms a heterocyclic group which is morpholyl, piperidyl,pyrrolidyl, or N-alkyl piperazyl; or

C(OH)R₁₀ R₁₁ where R₁₀ and R₁₁ are the same or different and representstraight or branched chain lower alkyl having 1-6 carbon atoms, phenyl,or phenylalkyl where each alkyl is straight or branched chain loweralkyl having 1-6 carbon atoms; and

R₃ and R₅ are the same or different and represent hydrogen or straightor branched chain lower alkyl having 1-6 carbon atoms.

These compounds are highly selective agonists, antagonists or inverseagonists for GABAa brain receptors or prodrugs of agonists, antagonistsor inverse agonists for GABAa brain receptors. These compounds areuseful in the diagnosis and treatment of anxiety, sleep, and seizuredisorders, overdose with benzodiazepine drugs, and enhancement ofmemory.

The compounds Formula I and their salts are suitable for the diagnosisand treatment of anxiety, Down Syndrome, sleep, cognitive and seizuredisorders, and overdose with benzodiazepine drugs and for enhancement ofalertness, both in human and non-human animals and domestic pets,especially dogs and cats and farm animals such as sheep, swine andcattle. Thus, the compounds of the invention are suitable for use inmethods for treating non-human animal or domestic pet, e.g., cattle ordogs, exhibiting symptoms of anxiety, such as restlessness or loss ofappetite during, for example, a thunderstorm, comprising administeringto the animal or pet an effective anxiolytic amount of a compound of theinvention or a salt thereof.

Thus, the invention provides methods for treating a subject non-humananimal or domestic pet exhibiting symptoms of anxiety comprisingadministering to the subject an effective anxiolytic amount of acompound of formula A or a pharmaceutically acceptable salt thereof,where formula A has the formula: ##STR9## or the pharmaceuticallyacceptable non-toxic salts thereof wherein: X is oxygen or sulfur;

W is

phenyl, thienyl, or pyridyl, or

phenyl, thienyl, or pyridyl, each of which may be mono or disubstitutedwith halogen, hydroxy, straight or branched chain lower alkyl having 1-6carbon atoms, amino, mono or dialkylamino where each alkyl is straightor branched chain lower alkyl having 1-6 carbon atoms, or straight orbranched chain lower alkoxy having 1-6 carbon atoms; ##STR10## wherein:A represents nitrogen or C--R₁ ;

B represents nitrogen or C--R₂ with the proviso that not both A and Bare nitrogen and not both A and B are carbon;

C represents nitrogen or C--R₁ ;

D represents nitrogen or C--R₂ with the proviso that not both C and Dare nitrogen;

E represents oxygen, sulfur or N--R₅ ;

R₁ and R₄ are the same or different and represent

hydrogen, halogen, straight or branched chain lower alkyl having 1-6carbon atoms, or straight or branched chain lower alkoxy having 1-6carbon atoms;

R₂ is

hydrogen, halogen, amino, phenyl, pyridyl, straight or branched chainlower alkyl having 1-6 carbon atoms, or phenylalkyl or pyridyalkyl whereeach alkyl is straight or branched chain lower alkyl having 1-6 carbonatoms, 1-indanyl, 4-(thia)deoxachromanyl,1-(1,2,3,4-tetrahydronaphthyl); 1-indanyl, 4-(thia)deoxachromanyl,1-(1,2,3,4-tetrahydronaphthyl), each of which is monosubstituted withhalogen, straight or branched chain lower alkyl having 1-6, carbonatoms, or straight or branched chain lower alkoxy having 1-6 carbonatoms;

OR₅, COR₅, CO₂ R₅, or OCOR₅, where R₅ is hydrogen, phenyl, pyridyl,straight or branched chain lower alkyl having 1-6 carbon atoms, orphenylalkyl or pyridylalkyl where each alkyl is straight or branchedchain lower alkyl having 1-6 carbon atoms;

--CONR₆ R₇ or --(CH₂)_(n) NR₆ R₇ where

n is 0, 1, or 2;

R₆ is hydrogen, straight or branched chain lower alkyl having 1-6 carbonatoms; and

R₇ is hydrogen, phenyl, pyridyl, straight or branched chain lower alkylhaving 1-6 carbon atoms, or phenylalkyl or pyridylalkyl where each alkylis straight or branched chain lower alkyl having 1-6 carbon atoms; or

NR₆ R₇ forms a heterocyclic group which is morpholyl, piperidyl,pyrrolidyl, or N-alkyl piperazyl; or

C(OH)R₁₀ R₁₁ where R₁₀ and R₁₁ are the same or different and representstraight or branched chain lower alkyl having 1-6 carbon atoms, phenyl,or phenylalkyl where each alkyl is straight or branched chain loweralkyl having 1-6 carbon atoms; and

R₃ and R₅ are the same or different and represent hydrogen or straightor branched chain lower alkyl having 1-6 carbon atoms.

BRIEF DESCRIPTION OF THE DRAWING

FIGS. 1A-1C show representative aryl fused imidazopyrimidines of thepresent invention.

DETAILED DESCRIPTION OF THE INVENTION

The novel compounds encompassed by the instant invention can bedescribed by the following general formula I: ##STR11## and thepharmaceutically acceptable non-toxic salts thereof wherein: X is oxygenor sulfur;

W is

phenyl, thienyl, or pyridyl, or

phenyl, thienyl, or pyridyl, each of which may be mono or disubstitutedwith halogen, hydroxy, straight or branched chain lower alkyl having 1-6carbon atoms, amino, mono or dialkylamino where each alkyl is straightor branched chain lower alkyl having 1-6 carbon atoms, or straight orbranched chain lower alkoxy having 1-6 carbon atoms; ##STR12## wherein:A represents nitrogen or C--R₁ ;

B represents nitrogen or C--R₂ with the proviso that not both A and Bare nitrogen;

C represents nitrogen or C--R₁ ;

D represents nitrogen or C--R₂ with the proviso that not both C and Dare nitrogen;

E represents oxygen, sulfur or N--R₅ ;

R₁ and R₄ are the same or different and represent

hydrogen, halogen, straight or branched chain lower alkyl having 1-6carbon atoms, or straight or branched chain lower alkoxy having 1-6carbon atoms;

R₂ is

hydrogen, halogen, hydroxy, amino, 1-indanyl, 4-(thia)deoxachromanyl,1-(1,2,3,4-tetrahydronaphthyl);

1-indanyl, 4-(thia)deoxachromanyl, 1-(1,2,3,4-tetrahydronaphthyl), eachof which is monosubstituted with halogen, straight or branched chainlower alkyl having 1-6, carbon atoms, or straight or branched chainlower alkoxy having 1-6 carbon atoms;

OR₅, COR₅, CO₂ R₅, OCOR₅, or R₅, where R₅ is hydrogen, phenyl, pyridyl,straight or branched chain lower alkyl having 1-6 carbon atoms, orphenylalkyl or pyridylalkyl where each alkyl is straight or branchedchain lower alkyl having 1-6 carbon atoms;

--CONR₆ R₇ or (CH₂)_(n) NR₆ R₇ where

n is 0, 1, or 2;

R₆ is hydrogen, straight or branched chain lower alkyl having 1-6 carbonatoms; and

R₇ is hydrogen, phenyl, pyridyl, straight or branched chain lower alkylhaving 1-6 carbon atoms, or phenylalkyl or pyridylalkyl where each alkylis straight or branched chain lower alkyl having 1-6 carbon atoms; or

NR₆ R₇ forms a heterocyclic group which is morpholyl, piperidyl,pyrrolidyl, or N-alkyl piperazyl; or

C(OH)R₁₀ R₁₁ where R₁₀ and R₁₁ are the same or different and representstraight or branched chain lower alkyl having 1-6 carbon atoms, phenyl,or phenylalkyl where each alkyl is straight or branched chain loweralkyl having 1-6 carbon atoms; and

R₃ and R₅ are the same or different and represent hydrogen or straightor branched chain lower alkyl having 1-6 carbon atoms.

In addition, the present invention encompasses compounds of Formula II.##STR13## wherein: W is

phenyl, thienyl, or pyridyl, or

phenyl, thienyl, or pyridyl, each of which may be mono or disubstitutedwith halogen, hydroxy, straight or branched chain lower alkyl having 1-6carbon atoms, amino, mono or dialkylamino where each alkyl is straightor branched chain lower alkyl having 1-6 carbon atoms, or straight orbranched chain lower alkoxy having 1-6 carbon atoms;

R₁ and R₄ are the same or different and represent

hydrogen, halogen, straight or branched chain lower alkyl having 1-6carbon atoms, or straight or branched chain lower alkoxy having 1-6carbon atoms;

R₂ is

hydrogen, halogen, hydroxy, amino, 1-indanyl, 4-(thia)deoxachromanyl,1-(1,2,3,4-tetrahydronaphthyl);

1-indanyl, 4-(thia)deoxachromanyl, 1-(1,2,3,4-tetrahydronaphthyl), eachof which is monosubstituted with halogen, straight or branched chainlower alkyl having 1-6, carbon atoms, or straight or branched chainlower alkoxy having 1-6 carbon atoms;

OR₅, COR₅, CO₂ R₅, OCOR₅, or R₅, where R₅ is hydrogen, phenyl, pyridyl,straight or branched chain lower alkyl having 1-6 carbon atoms, orphenylalkyl or pyridylalkyl where each alkyl is straight or branchedchain lower alkyl having 1-6 carbon atoms; or

--CONR₆ R₇ or --(CH₂)_(n) NR₆ R₇ where

n is 0, 1, or 2;

R₆ is hydrogen, straight or branched chain lower alkyl having 1-6 carbonatoms; and

R₇ is hydrogen, phenyl, pyridyl, straight or branched chain lower alkylhaving 1-6 carbon atoms, or phenylalkyl or pyridylalkyl where each alkylis straight or branched chain lower alkyl having 1-6 carbon atoms; or

NR₆ R₇ forms a heterocyclic group which is morpholyl, piperidyl,pyrrolidyl, or N-alkyl piperazyl; and

R₃ is hydrogen or straight or branched chain lower alkyl having 1-6carbon atoms.

The present invention also encompasses compounds of Formula III:##STR14## wherein: W is

phenyl, thienyl, or pyridyl, or

phenyl, thienyl, or pyridyl, each of which may be mono or disubstitutedwith halogen, hydroxy, straight or branched chain lower alkyl having 1-6carbon atoms, amino, mono or dialkylamino where each alkyl is straightor branched chain lower alkyl having 1-6 carbon atoms, or straight orbranched chain lower alkoxy having 1-6 carbon atoms;

R₁ and R₄ are the same or different and represent

hydrogen, halogen, straight or branched chain lower alkyl having 1-6carbon atoms, or straight or branched chain lower alkoxy having 1-6carbon atoms; and

R₃ is hydrogen or straight or branched chain lower alkyl having 1-6carbon atoms.

The present invention also encompasses compounds of Formula IV:##STR15## wherein: W is

phenyl, thienyl, or pyridyl, or

phenyl, thienyl, or pyridyl, each of which may be mono or disubstitutedwith halogen, hydroxy, straight or branched chain lower alkyl having 1-6carbon atoms, amino, mono or dialkylamino where each alkyl is straightor branched chain lower alkyl having 1-6 carbon atoms, or straight orbranched chain lower alkoxy having 1-6 carbon atoms;

E represents oxygen, sulfur, N--H, or N--Me;

R₁ represents

hydrogen, halogen, straight or branched chain lower alkyl having 1-6carbon atoms, or straight or branched chain lower alkoxy having 1-6carbon atoms; and

R₂ is

hydrogen, halogen, hydroxy, amino, 1-indanyl, 4-(thia)deoxachromanyl,1-(1,2,3,4-tetrahydronaphthyl);

1-indanyl, 4-(thia)deoxachromanyl, 1-(1,2,3,4-tetrahydronaphthyl), eachof which is monosubstituted with halogen, straight or branched chainlower alkyl having 1-6, carbon atoms, or straight or branched chainlower alkoxy having 1-6 carbon atoms;

OR₅, COR₅, CO₂ R₅, OCOR₅, or R₅, where R₅ is hydrogen, phenyl, pyridyl,straight or branched chain lower alkyl having 1-6 carbon atoms, orphenylalkyl or pyridylalkyl where each alkyl is straight or branchedchain lower alkyl having 1-6 carbon atoms; or

--CONR₆ R₇ or (CH₂)_(n) NR₆ R₇ where

n is 0, 1, or 2;

R₆ is hydrogen, straight or branched chain lower alkyl having 1-6 carbonatoms; and

R₇ is hydrogen, phenyl, pyridyl, straight or branched chain lower alkylhaving 1-6 carbon atoms, or phenylalkyl or pyridylalkyl where each alkylis straight or branched chain lower alkyl having 1-6 carbon atoms; or

NR₆ R₇ forms a heterocyclic group which is morpholyl, piperidyl,pyrrolidyl, or N-alkyl piperazyl.

The present invention also encompasses compounds of Formula V: ##STR16##wherein: W is

phenyl, thienyl, or pyridyl, or

phenyl, thienyl, or pyridyl, each of which may be mono or disubstitutedwith halogen, hydroxy, straight or branched chain lower alkyl having 1-6carbon atoms, amino, mono or dialkylamino where each alkyl is straightor branched chain lower alkyl having 1-6 carbon atoms, or straight orbranched chain lower alkoxy having 1-6 carbon atoms;

E represents oxygen, sulfur, N--H, or N--Me;

R₂ is

hydrogen, halogen, hydroxy, amino, 1-indanyl, 4-(thia)deoxachromanyl,1-(1,2,3,4-tetrahydronaphthyl);

1-indanyl, 4-(thia)deoxachromanyl, 1-(1,2,3,4-tetrahydronaphthyl), eachof which is monosubstituted with halogen, straight or branched chainlower alkyl having 1-6, carbon atoms, or straight or branched chainlower alkoxy having 1-6 carbon atoms;

OR₅, COR₅, CO₂ R₅, OCOR₅, or R₅, where R₅ is hydrogen, phenyl, pyridyl,straight or branched chain lower alkyl having 1-6 carbon atoms, orphenylalkyl or pyridylalkyl where each alkyl is straight or branchedchain lower alkyl having 1-6 carbon atoms; or

--CONR₆ R₇ or --CH₂)_(n) NR₆ R₇ where

n is 0, 1, or 2;

R₆ is hydrogen, straight or branched chain lower alkyl having 1-6 carbonatoms; and

R₇ is hydrogen, phenyl, pyridyl, straight or branched chain lower alkylhaving 1-6 carbon atoms, or phenylalkyl or pyridylalkyl where each alkylis straight or branched chain lower alkyl having 1-6 carbon atoms; or

NR₆ R₇ forms a heterocyclic group which is morpholyl, piperidyl,pyrrolidyl, or N-alkyl piperazyl; and

R₄ is hydrogen, halogen, straight or branched chain lower alkyl having1-6 carbon atoms, or straight or branched chain lower alkoxy having 1-6carbon atoms.

The present invention also encompasses compounds of Formula VI:##STR17## wherein: W is

phenyl, thienyl, or pyridyl, or

phenyl, thienyl, or pyridyl, each of which may be mono or disubstitutedwith halogen, hydroxy, straight or branched chain lower alkyl having 1-6carbon atoms, amino, mono or dialkylamino where each alkyl is straightor branched chain lower alkyl having 1-6 carbon atoms, or straight orbranched chain lower alkoxy having 1-6 carbon atoms.

E represents oxygen, sulfur, N--H, or N--Me; and

R₁ and R₄ are the same or different and represent

hydrogen, halogen, straight or branched chain lower alkyl having 1-6carbon atoms, or straight or branched chain lower alkoxy having 1-6carbon atoms.

Non-toxic pharmaceutical salts include salts of acids such ashydrochloric, phosphoric, hydrobromic, sulfuric, sulfinic, formic,toluene sulfonic, hydroiodic, acetic and the like. Those skilled in theart will recognize a wide variety of non-toxic pharmaceuticallyacceptable addition salts.

Representative compounds of the present invention, which are encompassedby Formula I, include, but are not limited to the compounds in FIG. 1and their pharmaceutically acceptable salts. The present invention alsoencompasses the acylated prodrugs of the compounds of Formula I. Thoseskilled in the art will recognize various synthetic methodologies whichmay be employed to prepare non-toxic pharmaceutically acceptableaddition salts and acylated prodrugs of the compounds encompassed byFormula I.

By lower alkyl in the present invention is meant straight or branchedchain alkyl groups having 1-6 carbon atoms, such as, for example,methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl,pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and3-methylpentyl.

By lower alkoxy in the present invention is meant straight or branchedchain alkoxy groups having 1-6 carbon atoms, such as, for example,methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy,pentoxy, 2-pentyl, isopentoxy, neopentoxy, hexoxy, 2-hexoxy, 3-hexoxy,and 3-methylpentoxy.

By halogen in the present invention is meant fluorine, bromine,chlorine, and iodine.

By N-alkylpiperazyl in the invention is meant radicals of the formula:##STR18## where R is a straight or branched chain lower alkyl as definedabove.

By 4-(thia)deoxachromanyl is meant a radical of the formula: ##STR19##

The pharmaceutical utility of compounds of this invention are indicatedby the following assay for GABAa receptor activity.

Assays are carried out as described in Thomas and Tallman (J. Bio. Chem.156: 9838-9842. J. Neurosci. 3:433-440, 1983). Rat cortical tissue isdissected and homogenized in 25 volumes (w/v) of 0.05 M Tris HCl buffer(pH 7.4 at 4° C.). The tissue homogenate is centrifuged in the cold (4°)at 20,000× g for 20'. The supernatant is decanted and the pellet isrehomogenized in the same volume of buffer and again centrifuged at20,000× g. The supernatant is decanted and the pellet is frozen at -20°C. overnight. The pellet is then thawed and rehomogenized in 25 volume(original wt/vol) of buffer and the procedure is carried out twice. Thepellet is finally resuspended in 50 volumes (w/vol of 0.05 M Tris HClbuffer (pH 7.4 at 40° C.).

Incubations contain 100 ml of tissue homogenate, 100 ml of radioligand0.5 nM (³ H--RO15-1788 [³ H-Flumazenil] specific activity 80 Ci/mmol),drug or blocker and buffer to a total volume of 500 ml. Incubations arecarried for 30 min at 4° C. then are rapidly filtered through GFBfilters to separate free and bound ligand. Filters are washed twice withfresh 0.05 M Tris HCl buffer (pH 7.4 at 4° C.) and counted in a liquidscintillation counter. 1.0 mM diazepam is added to some tubes lodetermine nonspecific binding. Data are collected in triplicatedeterminations, averaged and % inhibition of total specific binding iscalculated. Total Specific Binding=Total-Nonspecific. In some cases, theamounts of unlabeled drugs is varied and total displacement curves ofbinding are carried out. Data are converted to a form for thecalculation of IC₅₀ and Hill Coefficient (nH). Data for the compounds ofthis invention are listed in Table 1.

                  TABLE I                                                         ______________________________________                                        Compound Number.sup.1                                                                          IC.sub.50 (μM)                                            ______________________________________                                        1                0.042                                                          2 0.169                                                                       15  0.132                                                                   ______________________________________                                    

The compounds of general formula I may be administered orally,topically, parenterally, by inhalation or spray or rectally in dosageunit formulations containing conventional non-toxic pharmaceuticallyacceptable carriers, adjuvants and vehicles. The term parenteral as usedherein includes subcutaneous injections, intravenous, intramuscular,intrasternal injection or infusion techniques. In addition, there isprovided a pharmaceutical formulation comprising a compound of generalformula I and a pharmaceutically acceptable carrier. One or morecompounds of general formula I may be present in association with one ormore non-toxic pharmaceutically acceptable carriers and/or diluentsand/or adjuvants and if desired other active ingredients. Thepharmaceutical compositions containing compounds of general formula Imay be in a form suitable for oral use, for example, as tablets,troches, lozenges, aqueous or oily suspensions, dispersible powders orgranules, emulsion, hard or soft capsules, or syrups or elixirs.

Compositions intended for oral use may be prepared according to anymethod known to the art for the manufacture of pharmaceuticalcompositions and such compositions may contain one or more agentsselected from the group consisting of sweetening agents, flavoringagents, coloring agents and preserving agents in order to providepharmaceutically elegant and palatable preparations. Tablets contain theactive ingredient in admixture with non-toxic pharmaceuticallyacceptable excipients which are suitable for the manufacture of tablets.These excipients may be for example, inert diluents, such as calciumcarbonate, sodium carbonate, lactose, calcium phosphate or sodiumphosphate; granulating and disintegrating agents, for example, cornstarch, or alginic acid; binding agents, for example starch, gelatin oracacia, and lubricating agents, for example magnesium stearate, stearicacid or talc. The tablets may be uncoated or they may be coated by knowntechniques to delay disintegration and absorption in thegastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonosterate or glyceryl distearate may be employed.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredient is mixed with water or anoil medium, for example peanut oil, liquid paraffin or olive oil.

Aqueous suspensions contain the active materials in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydropropylmethylcellulose,sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example, lecithin, or condensation products of an alkylene oxidewith fatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphalic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl p-hydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agents,such as sucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredientsin a vegetable oil, for example arachis oil, olive oil, sesame oil orcoconut oil, or in a mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set forthabove, and flavoring agents may be added to provide palatable oralpreparations. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example sweetening, flavoring and coloringagents, may also be present.

Pharmaceutical compositions of the invention may also be in the form ofoil-in-water emulsions. The oily phase may be a vegetable oil, forexample olive oil or arachis oil, or a mineral oil, for example liquidparaffin or mixtures of these. Suitable emulsifying agents may benaturally-occurring gums, for example gum acacia or gum tragacanth,naturally-occurring phosphatides, for example soy bean, lecithin, andesters or partial esters derived from fatty acids and hexitol,anhydrides, for example sorbitan monoleate, and condensation products ofale said partial esters with ethylene oxide, for example polyoxyethylenesorbitan monoleate. The emulsions may also contain sweetening andflavoring agents.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitor or sucrose. Such formulations mayalso contain a demulcent, a preservative and flavoring and coloringagents. The pharmaceutical compositions may be in the form of a sterileinjectable aqueous or oleaginous suspension. This suspension may beformulated according to the known art using those suitable dispersing orwetting agents and suspending agents which have been mentioned above.The sterile injectable preparation may also be sterile injectablesolution or suspension in a non-toxic parentally acceptable diluent orsolvent, for example as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that may be employed are water.Ringer's solution and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose any bland fixed oil may be employedincluding synthetic mono-or diglycerides. In addition, fatty acids suchas oleic acid find use in the preparation of injectables.

The compounds of general formula I may also be administered in the formof suppositories for rectal administration of the drug. Thesecompositions can be prepared by mixing the drug with a suitablenon-irritating excipient which is solid at ordinary temperatures butliquid at the rectal temperature and will therefore melt in the rectumto release the drug. Such materials are cocoa butter and polyethyleneglycols.

Compounds of general formula I may be administered parenterally in asterile medium. The drug, depending on the vehicle and concentrationused, can either be suspended or dissolved in the vehicle.Advantageously, adjuvants such as local anaesthetics, preservatives andbuffering agents can be dissolved in the vehicle.

Dosage levels of the order of from about 0.1 mg to about 140 mg perkilogram of body weight per day arc useful in the treatment of theabove-indicated conditions (about 0.5 mg to about 7 g per patient perday). The amount of active ingredient that may be combined with thecarrier materials to produce a single dosage form will vary dependingupon the host treated and the particular mode of administration. Dosageunit forms will generally contain between from about 1 mg to about 500mg of an active ingredient.

It will be understood, however, that the specific dose level for anyparticular patient will depend upon a variety of factors including theactivity of the specific compound employed, the age, body weight,general health, sex, diet, time of administration, route ofadministration, and rate of excretion, drug combination and the severityof the particular disease undergoing therapy.

An illustration of the preparation of compounds of the present inventionis given in Schemes I and II. Those having skill in the art willrecognize that the starting materials may be varied and additional stepsemployed to produce compounds encompassed by the present invention, asdemonstrated by the following examples. ##STR20## wherein

X is oxygen or sulfur;

W is

phenyl, thienyl, or pyridyl, or

phenyl, thienyl, or pyridyl, each of which may be mono or disubstitutedwith halogen, hydroxy, straight or branched chain lower alkyl having 1-6carbon atoms, amino, mono or dialkylamino where each alkyl is straightor branched chain lower alkyl having 1-6 carbon atoms, or straight orbranched chain lower alkoxy having 1-6 carbon atoms; ##STR21## wherein:A represents nitrogen or C--R₁ ;

B represents nitrogen or C--R₂ with the proviso that not both A and Bare nitrogen and not both A and B are carbon;

C represents nitrogen or C--R₁ ;

D represents nitrogen or C--R₂ with the proviso that not both C and Dare nitrogen;

E represents oxygen, sulfur or N--R₅ ;

R₁ and R₄ are the same or different and represent

hydrogen, halogen, straight or branched chain lower alkyl having 1-6carbon atoms, or straight or branched chain lower alkoxy having 1-6carbon atoms;

R₂ is

hydrogen, halogen, hydroxy, amino, 1-indanyl, 4-(thia)deoxachromanyl,1-(1,2,3,4-tetrahydronaphthyl);

1-indanyl, 4-(thia)deoxachromanyl, 1-(1,2,3,4-tetrahydronaphthyl), eachof which is monosubstituted with halogen, straight or branched chainlower alkyl having 1-6, carbon atoms, or straight or branched chainlower alkoxy having 1-6 carbon atoms;

OR₅, COR₅, CO₂ R₅, OCOR₅, or R₅ where R₅ is hydrogen, phenyl, pyridyl,straight or branched chain lower alkyl having 1-6 carbon atoms, orphenylalkyl or pyridylalkyl where each alkyl is straight or branchedchain lower alkyl having 1-6 carbon atoms;

--CONR₆ R₇ or --(CH₂)_(n) NR₆ R₇ where

n is 0, 1, or 2;

R₆ is hydrogen, straight or branched chain lower alkyl having 1-6 carbonatoms; and

R₇ is hydrogen, phenyl, pyridyl, straight or branched chain lower alkylhaving 1-6 carbon atoms, or phenylalkyl or pyridylalkyl where each alkylis straight or branched chain lower alkyl having 1-6 carbon atoms; or

NR₆ R₇ forms a heterocyclic group which is morpholyl, piperidyl,pyrrolidyl, or N-alkyl piperazyl; or

C(OH)R₁₀ R₁₁ where R₁₀ and R₁ are the same or different and representstraight or branched chain lower alkyl having 1-6 carbon atoms, phenyl,or phenylalkyl where each alkyl is straight or branched chain loweralkyl having 1-6 carbon atoms; and

R₃ and R₅ are the same or different and represent hydrogen or straightor branched chain lower alkyl having 1-6 carbon atoms.

Those having skill in the art will recognize that the starting materialsmay be varied and additional steps employed to produce compoundsencompassed by the present invention, as demonstrated by the followingexamples. In some cases protection of certain reactive functionalitiesmay be necessary to achieve some of the above transformations. Ingeneral the need for such protecting groups will be obvious to thoseskilled in the art of organic synthesis as well as the conditionsnecessary to attach and remove such groups.

The invention is illustrated further by the following examples which arenot to be construed as limiting the invention in scope or spirit to thespecific procedures described in them.

EXAMPLE I ##STR22##

To a stirred suspension of 4-Amino-3-cyano-1,2,5,6-tetrahydropyridine(prepared according to a the procedure described by Taub et al., 1967,J. Chem. Soc. C: 1558) (95.51 g, 775 mmol) in pyridine (500 mL), benzoicanhydride (274 g, 1.20 mol) was added in portions over 1-2 hours. Afterstirring an additional 30 minutes, the precipitate was collected, washedfirst with toluene, then ether, and subsequently allowed to dry toafford 1-benzoyl-4-amino-3-cyano-1,2,5,6-tetrahydropyridine as a whitesolid, m.p. 178-181° C.

EXAMPLE II ##STR23##

A slurry of 1-benzoyl-4-amino-3-cyano-1,2,5,6-tetrahydropyridine (35.23g, 155 mmol) and urea (46.55 g, 775 mmol) in 2-(2-ethoxyethoxy)ethanol(75 mL) was gradually heated to about 205° C., and maintained at 205° C.for 90 minutes. Heating was ceased and hot water was carefully addedwhile shaking the mixture. The mixture was vacuum filtered to collectthe precipitate while hot. The precipitate was washed with hot wateruntil the filtrate was colorless. The precipitate was then washed withethanol until the filtrate was colorless, and then finally with ethylacetate and allowed to dry to yield6-benzoyl-4-amino-6,7,8,9-tetrahydro-pyrido[3,4-e]pyrimidin-2-one as alight yellow solid.

EXAMPLE III ##STR24##

A mixture of6-benzoyl-4-amino-6,7,8,9-tetrahydro-pyrido[3,4-e]pyrimidin-2-one (1 g,3.7 mmol) and 1-bromo-2'-fluoroacetophenone (0.74 g, 3.7 mmol) in 8 mLof dimethylformamide (DMF) was heated at about 150° C. for 45 minutes.The reaction mixture was poured into ice water and the precipitatecollected to give9-Benzoyl-2-(2-fluorophenyl)-7,8,9,10-tetrabydro-imidazo[1,2-c]pyrido[3,4-e]pyrimidin-5(6H)-one. Later, a second crop of precipitate was collectedas a cream-colored solid, m.p. 269-271° C. (d).

EXAMPLE IV ##STR25##

To a solution of9-Benzoyl-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]pyrido[3,4-e]pyrimidin-5(6H)-one(435 mg, 1.1 mmol) in ethanol (5 mL) was added 5 mL of 50% aqueoussodium hydroxide. The mixture was refluxed for about 1 hour, and thenpoured into saturated aqueous ammonium chloride and extracted twice with10% methanol/ethyl acetate. The combined organic layers were dried overmagnesium sulfate, filtered, concentrated, and triturated withmethanol/ether to give2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]pyrido[3,4-e]pyrimidin-5(6H)-one,m.p.>310° C.

EXAMPLE V ##STR26##

A mixture of2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]pyrido[3,4-e]pyrimidin-5(6H)-one(110 mg) and palladium black (150 mg) was placed in a sublimator andevacuated (1 mm Hg). The temperature was slowly raised to 280° C. Thedesired product sublimed from the mixture and was collected after theapparatus had been cooled back down to room temperature. In this manner2-(2-Fluorophenyl)-imidazo[1,2-c]pyrido[3,4-e]pyrimidin-5(6H)-one(Compound 1), m.p. 315-320° C. was obtained as tan crystals.

EXAMPLE VI

The following compounds were prepared essentially according to theprocedures described in Examples I-V:

(a) 2-Phenyl-imidazo[1,2-c]pyrido[3,4-e]pyrimidin-5(6H)-one (Compound2), m.p. 295-300° C.

(b) 2-(3-Fluorophenyl)-imidazo[1,2-c]pyrido[3,4-e]pyrimidin-5(6H)-one(Compound 3).

(c) 2-(4-Fluorophenyl)-imidazo[1,2-c]pyrido[3,4-e]pyrimidin-5(6H)-one(Compound 4), m.p. 365-368° C.

(d) 2-(3-Methoxyphenyl)-imidazo[1,2-c]pyrido[3,4-e]pyrimidin-5(6H)-one(Compound 5).

(e) 2-(4-Methoxyphenyl)-imidazo[1,2-c]pyrido[3,4-e]pyrimidin-5(6H)-one(Compound 6), m.p. 270-275° C.

(f)2-(2-Fluoro-3-methoxyphenyl)-imidazo[1,2-c]pyrido[3,4-e]pyrimidin-5(6H)-one(Compound 7).

(g)2-(2-Fluoro-4-methoxyphenyl)-imidazo[1,2-c]pyrido[3,4-e]pyrimidin-5(6H)-one(Compound 8).

(h)2-(2-Fluoro-5-methoxyphenyl)-imidazo[1,2-c]pyrido[3,4-e]pyrimidin-5(6H)-one(Compound 9).

(i)2-(2-Fluoro-4-ethoxyphenyl)-imidazo[1,2-c]pyrido[3,4-e]pyrimidin-5(6H)-one(Compound 10).

(j) 2-(4-Ethoxyphenyl)-imidazo[1,2-c]pyrido[3,4-e]pyrimidin-5(6H)-one(Compound 11).

(k) 2-(4-Methylphenyl)-imidazo[1,2-c]pyrido[3,4-e]pyrimidin-5(6H)-one(Compound 12).

(l) 2-(4-Chlorophenyl)-imidazo[1,2-c]pyrido[3,4-e]pyrimidin-5(6H)-one(Compound 13).

(m) 2-(3-Chlorophenyl)-imidazo[1,2-c]pyrido[3,4-e]pyrimidin-5(6H)-one(Compound 14).

EXAMPLE VI ##STR27##

A mixture of 3-Amino-2-chloro-pyridine (5 g) and cuprous cyanide (5 g)in 10 mL of N-Methylpyrrolidone was heated with stirring at 185° C. for2 h under an atmosphere of nitrogen. The reaction mixture wasconcentrated in vacuo and concentrated ammonium hydroxide and 10%methanol/methylene chloride were added. The mixture was shaken andfiltered, the organic layer separated and the aqueous layer extractedtwo times with methanol/methylene chloride. The combined organicextracts were dried over magnesium sulfate and the solvent removed invacuo. The residue was recrystallized from ethyl acetate/hexane toafford 3-Amino-2-cyanopyridine as a tan solid.

EXAMPLE VII ##STR28##

A slurry of 3-Amino-2-cyanopyridine (200 mg) and urea (400 mg) in2-(2-ethoxyethoxy)ethanol (0.5 mL) was gradually heated to about 205°C., and maintained at 205° C. for 10 min. Heating was ceased and 6 mL ofhot water was carefully added while shaking the mixture. The mixture wasvacuum filtered to collect the precipitate. The precipitate was washedwith water and ethyl acetate and allowed to dry to yield4-Amino-pyrido[2,3-e]pyrimidin-2-one as a light yellow solid, m.p. >300°C.

EXAMPLE VIII ##STR29##

A mixture of 4-Amino-pyrido[2,3-e]pyrimidin-2-one (95 mg) andα-bromo-acetophenone (117 mg) in 4 mL of dimethylformamide (DMF) washeated at about 150° C. for 20 min. The reaction mixture wasconcentrated in vacuo and the residue was subjected to flashchromatography on silica gel with 10% methanol/methylene chloride as theeluent to afford2-Phenyl-imidazo[1,2-c]pyrido[2,3-e]pyrimidin-5(6H)-one. (Compound 15),m.p. 329-330° C.

EXAMPLE IX

The following compounds were prepared essentially according to theprocedures described in Examples VI-VIII:

(a) 2-(2-Fluorophenyl)-imidazo[1,2-c]pyrido[2,3-e]pyrimidin-5(6H)-one(Compound 16), m.p. 374-377° C.

(b) 2-(3-Fluorophenyl)-imidazo[1,2-c]pyrido[2,3-c]pyrimidin-5(6H)-one(Compound 17).

(c) 2-(4-Fluorophenyl)-imidazo[1,2-c]pyrido[2,3-e]pyrimidin-5(6H)-one(Compound 18).

(d) 2-(3-Methoxyphenyl)-imidazo[1,2-c]pyrido[2,3-e]pyrimidin-5(6H)-one(Compound 19).

(e) 2-(4-Methoxyphenyl)-imidazo[1,2-c]pyrido[2,3-e]pyrimidin-5(6H)-one(Compound 20), m.p. 343-345° C.

(f)2-(2-Fluoro-3-methoxyphenyl)-imidazo[1,2-c]pyrido[2,3-e]pyrimidin-5(6H)-one(Compound 21).

(g)2-(2-Fluoro-4-methoxyphenyl)-imidazo[1,2-c]pyrido[2,3-e]pyrimidin-5(6H)-one(Compound 22), m.p. >330° C.

(h)2-(2-Fluoro-5-methoxyphenyl)-imidazo[1,2-c]pyrido[2,3-e]pyrimidin-5(6H)-one(Compound 23).

(i)2-(2-Fluoro-4-ethoxyphenyl)-imidazo[1,2-c]pyrido[2,3-e]pyrimidin-5(6H)-one(Compound 24).

(j) 2-(4-Ethoxyphenyl)-imidazo[1,2-c]pyrido[2,3-e]pyrimidin-5(6H)-one(Compound 25).

(k) 2-(4-Methylphenyl)-imidazo[1,2-c]pyrido[2,3-e]pyrimidin-5(6H)-one(Compound 26).

(l) 2-(4-Chlorophenyl)-imidazo[1,2-c]pyrido[2,3-e]pyrimidin-5(6H)-one(Compound 27).

(m) 2-(3-Chlorophenyl)-imidazo[1,2-c]pyrido[2,3-e]pyrimidin-5(6H)-one(Compound 28).

(n)7,8-Dimethyl-2-(4-methoxyphenyl)-imidazo[1,2-c]imidazo[4,5-e]pyrimidin-5(6H)-one(Compound 29).

(o) 2-(4-Methoxyphenyl)-imidazo[1,2-c]thieno[3,2-e]pyrimidin-5(6H)-one(Compound 30).

(p)2-(2-Fluoro-4-methoxyphenyl)-imidazo[1,2-c]thieno[3,2-e]pyrimidin-5(6H)-one(Compound 31).

(q) 2-(4-Methoxyphenyl)-imidazo[1,2-c]thieno[2,3-e]pyrimidin-5(6H)-one(Compound 32).

(r)2-(2-Fluoro-4-methoxyphenyl)-imidazo[1,2-c]thieno[2,3-e]pyrimidin-5(6H)-one(Compound 33).

(s) 2-(4-Methoxyphenyl)-imidazo[1,2-c]thieno[3,4-e]pyrimidin-5(6H)-one(Compound 34).

(t)2-(2-Fluoro-4-methoxyphenyl)-imidazo[1,2-c]thieno[3,4-e]pyrimidin-5(6H)-one(Compound 35).

(u)2-(2-Fluoro-4-methoxyphenyl)-imidazo[1,2-c]oxazolo[2,3-e]pyrimidin-5(6H)-one(Compound 36).

(v)2-(2-Fluoro-4-methoxyphenyl)-imidazo[1,2-c]thiazolo[4,5-e]pyrimidin-5(6H)-one(Compound 37).

(w)2-(2-Fluoro-4-methoxyphenyl)-7-methyl-imidazo[1,2-c]pyrazolo[4,5-e]pyrimidin-5(6H)-one(Compound 38).

The invention and the manner and process of making and using it, are nowdescribed in such full, clear, concise and exact terms as to enable anyperson skilled in the art to which it pertains, to make and use thesame. It is to be understood that the foregoing describes preferredembodiments of the present invention and that modifications may be madetherein without departing from the spirit or scope of the presentinvention as set forth in the claims. To particularly point out anddistinctly claim the subject matter regarded as invention, the followingclaims conclude this specification.

What is claimed is:
 1. A method for treating a subject non-human animalor domestic pet exhibiting symptoms of anxiety comprising administeringto the subject an effective anxiolytic amount of a compound of formula Aor a pharmaceutically acceptable salt thereof, where formula A has theformula: ##STR30## or the pharmaceutically acceptable non-toxic saltsthereof wherein: X is oxygen or sulfur;W isphenyl, thienyl, or pyridyl,or phenyl, thienyl, or pyridyl, each of which may be mono ordisubstituted with halogen, hydroxy, straight or branched chain loweralkyl having 1-6 carbon atoms, amino, mono or dialkylamino where eachalkyl is straight or branched chain lower alkyl having 1-6 carbon atoms,or straight or branched chain lower alkoxy having 1-6 carbon atoms;##STR31## wherein: A represents nitrogen or C--R₁ ; B representsnitrogen or C--R₂ with the proviso that not both A and B are nitrogenand not both A and B are carbon; C represents nitrogen or C--R₁ ; Drepresents nitrogen or C--R₂ with the proviso that not both C and D arenitrogen; E represents oxygen, sulfur or N--R₅ ; R₁ and R₄ are the sameor different and representhydrogen, halogen, straight or branched chainlower alkyl having 1-6 carbon atoms, or straight or branched chain loweralkoxy having 1-6 carbon atoms; R₂ ishydrogen, halogen, amino, phenyl,pyridyl, straight or branched chain lower alkyl having 1-6 carbon atoms,or phenylalkyl or pyridyalkyl where each alkyl is straight or branchedchain lower alkyl having 1-6 carbon atoms, 1-indanyl,1-(1,2,3,4-tetrahydronaphthyl); 1-indanyl or1-(1,2,3,4-tetrahydronaphthyl), each of which is monosubstituted withhalogen, straight or branched chain lower alkyl having 1-6, carbonatoms, or straight or branched chain lower alkoxy having 1-6 carbonatoms; OR₅, COR₅, CO₂ R₅, or OCOR₅, where R₅ is hydrogen, phenyl,pyridyl, straight or branched chain lower alkyl having 1-6 carbon atoms,or phenylalkyl or pyridylalkyl where each alkyl is straight or branchedchain lower alkyl having 1-6 carbon atoms; --CONR₆ R₇ or --(CH₂)_(n) NR₆R₇ wheren is 0, 1, or 2; R₆ is hydrogen, straight or branched chainlower alkyl having 1-6 carbon atoms; and R₇ is hydrogen, phenyl,pyridyl, straight or branched chain lower alkyl having 1-6 carbon atoms,or phenylalkyl or pyridylalkyl where each alkyl is straight or branchedchain lower alkyl having 1-6 carbon atoms; or NR₆ R₇ forms aheterocyclic group which is morpholyl, piperidyl, pyrrolidyl, or N-alkylpiperazyl; or C(OH)R₁₀ R₁₁ where R₁₀ and R₁₁ are the same or differentand represent straight or branched chain lower alkyl having 1-6 carbonatoms, phenyl, or phenylalkyl where each alkyl is straight or branchedchain lower alkyl having 1-6 carbon atoms; and R₃ and R₅ are the same ordifferent and represent hydrogen or straight or branched chain loweralkyl having 1-6 carbon atoms.
 2. A method according to claim 1, whereinFormula A has the formula: ##STR32## wherein: W isphenyl, thienyl, orpyridyl, or phenyl, thienyl, or pyridyl, each of which may be mono ordisubstituted with halogen, hydroxy, straight or branched chain loweralkyl having 1-6 carbon atoms, amino, mono or dialkylamino where eachalkyl is straight or branched chain lower alkyl having 1-6 carbon atoms,or straight or branched chain lower alkoxy having 1-6 carbon atoms; R₄representshydrogen, halogen, straight or branched chain lower alkylhaving 1-6 carbon atoms, or straight or branched chain lower alkoxyhaving 1-6 carbon atoms; R₂ ishydrogen, halogen, hydroxy, amino, phenyl,pyridyl, straight or branched chain lower alkyl having 1-6 carbon atoms,or phenylalkyl or pyridylalkyl where each alkyl is straight or branchedchain lower alkyl having 1-6 carbon atoms, 1-indanyl,1-(1,2,3,4-tetrahydronaphthyl); 1-indanyl or1-(1,2,3,4-tetrahydronaphthyl), each of which is monosubstituted withhalogen, straight or branched chain lower alkyl having 1-6, carbonatoms, or straight or branched chain lower alkoxy having 1-6 carbonatoms; OR₅, COR₅, CO₂ R₅, OCOR₅, or R₅, where R₅ is hydrogen, phenyl,pyridyl, straight or branched chain lower alkyl having 1-6 carbon atoms,or phenylalkyl or pyridyalkyl where each alkyl is straight or branchedchain lower alkyl having 1-6 carbon atoms; or --CONR₆ R₇ or --(CH₂)_(n)NR₆ R₇ wheren is 0, 1, or 2; R₆ is hydrogen, straight or branched chainlower alkyl having 1-6 carbon atoms; and R₇ is hydrogen, phenyl,pyridyl, straight or branched chain lower alkyl having 1-6 carbon atoms,or phenylalkyl or pyridylalkyl where each alkyl is straight or branchedchain lower alkyl having 1-6 carbon atoms; or NR₆ R₇ forms aheterocyclic group which is morpholyl, piperidyl, pyrrolidyl, or N-alkylpiperazyl; and R₃ is hydrogen or straight or branched chain lower alkylhaving 1-6 carbon atoms.
 3. A method according to claim 1, whereinFormula A has the formula: ##STR33## wherein: W isphenyl, thienyl, orpyridyl, or phenyl, thienyl, or pyridyl, each of which may be mono ordisubstituted with halogen, hydroxy, straight or branched chain loweralkyl having 1-6 carbon atoms, amino, mono or dialkylamino where eachalkyl is straight or branched chain lower alkyl having 1-6 carbon atoms,or straight or branched chain lower alkoxy having 1-6 carbon atoms; R₁and R₄ are the same or different and represent hydrogen, halogen,straight or branched chain lower alkyl having 1-6 carbon atoms, orstraight or branched chain lower alkoxy having 1-6 carbon atoms; and R₃is hydrogen or straight branched chain lower alkyl having 1-6 carbonatoms.
 4. A method according to claim 1, wherein Formula A has theformula: ##STR34## wherein: W isphenyl, thienyl, or pyridyl, or phenyl,thienyl, or pyridyl, each of which may be mono or disubstituted withhalogen, hydroxy, straight or branched chain lower alkyl having 1-6carbon atoms, amino, mono or dialkylamino where each alkyl is straightor branched chain lower alkyl having 1-6 carbon atoms, or straight orbranched chain lower alkoxy having 1-6 carbon atoms; E representsoxygen, sulfur, N--H, or N--Me; R₁ representshydrogen, halogen, straightor branched chain lower alkyl having 1-6 carbon atoms, or straight orbranched chain lower alkoxy having 1-6 carbon atoms; and R₂ ishalogen,amino, 1-indanyl, 1-(1,2,3,4-tetrahydronaphthyl); 1-indanyl or1-(1,2,3,4-tetrahydronaphthyl), each of which is monosubstituted withhalogen, straight or branched chain lower alkyl having 1-6, carbonatoms, or straight or branched chain lower alkoxy having 1-6 carbonatoms; OR₅, COR₅, CO₂ R₅, OCOR₅, or R₅, where R₅ is hydrogen, phenyl,pyridyl, straight or branched chain lower alkyl having 1-6 carbon atoms,or phenylalkyl where each alkyl is straight or branched chain loweralkyl having 1-6 carbon atoms; --CONR₆ R₇ or --(CH₂)_(n) NR₆ R₇ wherenis 0, 1, or 2; R₆ is hydrogen, straight or branched chain lower alkylhaving 1-6 carbon atoms; and R₇ is hydrogen, phenyl, pyridyl, straightor branched chain lower alkyl having 1-6 carbon atoms, or phenylalkyl orpyridylalkyl where each alkyl is straight or branched chain lower alkylhaving 1-6 carbon atoms; or NR₆ R₇ forms a heterocyclic group which ismorpholyl, piperidyl, pyrrolidyl, or N-alkyl piperazyl.
 5. A methodaccording to claim 1, wherein Formula A has the formula: ##STR35##wherein: W isphenyl, thienyl, or pyridyl, or phenyl, thienyl, orpyridyl, each of which may be mono or disubstituted with halogen,hydroxy, straight or branched chain lower alkyl having 1-6 carbon atoms,amino, mono or dialkylamino where each alkyl is straight or branchedchain lower alkyl having 1-6 carbon atoms, or straight or branched chainlower alkoxy having 1-6 carbon atoms; E represents oxygen, sulfur, N--H,or N--Me; R₂ ishalogen, amino, 1-indanyl,1-(1,2,3,4-tetrahydronaphthyl); 1-indanyl or1-(1,2,3,4-tetrahydronaphthyl), each of which is monosubstituted withhalogen, straight or branched chain lower alkyl having 1-6, carbonatoms, or straight or branched chain lower alkoxy having 1-6 carbonatoms; OR₅, COR₅, CO₂ R₅, OCOR₅, or R₅, where R₅ is hydrogen, phenyl,pyridyl, straight or branched chain lower alkyl having 1-6 carbon atoms,or phenylalkyl or pyridyalkyl where each alkyl is straight or branchedchain lower alkyl having 1-6 carbon atoms; --CONR₆ R₇ or --(CH₂)_(n) NR₆R₇ wheren is 0, 1, or 2; R₆ is hydrogen, straight or branched chainlower alkyl having 1-6 carbon atoms; and R₇ is hydrogen, phenyl,pyridyl, straight or branched chain lower alkyl having 1-6 carbon atoms,or phenylalkyl or pyridylalkyl where each alkyl is straight or branchedchain lower alkyl having 1-6 carbon atoms; or NR₆ R₇ forms aheterocyclic group which is morpholyl, piperidyl, pyrrolidyl, or N-alkylpiperazyl; and R₄ is hydrogen, halogen, straight or branched chain loweralkyl having 1-6 carbon atoms, or straight or branched chain loweralkoxy having 1-6 carbon atoms.
 6. A method according to claim 1,wherein Formula A has the formula: ##STR36## wherein W isphenyl,thienyl, or pyridyl, or phenyl, thienyl, or pyridyl, each of which maybe mono or disubstituted with halogen, hydroxy, straight or branchedchain lower alkyl having 1-6 carbon atoms, amino, mono or dialkylaminowhere each alkyl is straight or branched chain lower alkyl having 1-6carbon atoms, or straight or branched chain lower alkoxy having 1-6carbon atoms; E represents oxygen, sulfur, N--H, or N--Me; R₁ and R₄ arethe same or different and represent hydrogen, halogen, straight orbranched chain lower alkyl having 1-6 carbon atoms, or straight orbranched chain lower alkoxy having 1-6 carbon atoms.
 7. A methodaccording to claim 1, wherein Formula A is2-(2-Fluorophenyl)imidazo[1,2-c]pyrido[3,4-e]pyrimidin-5 (6H)-one.
 8. Amethod according to claim 1, wherein Fomula A is2-Phenyl-imidazo[1,2-c]pyrido[3,4-e]pyrimidin-5 (6H)-one.
 9. A methodaccording to claim 1, wherein Formula A is2-(3-Fluorophenyl)imidazo[1,2-c]pyrido[3,4-e]pyrimidin-5 (6H)-one.
 10. Amethod according to claim 1, wherein Formula A is2-(4-Fluorophenyl)imidazo[1,2-c]pyrido[3,4-e]pyrimidin-5 (6H)-one.
 11. Amethod according to claim 1, wherein Formula A is2-(3-Methoxyphenyl)imidazo[1,2-c]pyrido[3,4-e]pyrimidin-5 (6H)-one. 12.A method according to claim 1, wherein Formula A is2-(3-Methoxyphenyl)imidazo[1,2-c]pyrido[3,4-e]pyrimidin-5 (6H)-one. 13.A method according to claim 1, wherein Formula A is2-(3-Fluoro-3-methoxyphenyl)imidazo[1,2-c]pyrido[3,4-e]pyrimidin-5(6H)-one.
 14. A method according to claim 1, wherein Formula A is2-(2-Fluoro-4-methoxyphenyl)imidazo[1,2-c]pyrido[3,4-e]pyrimidin-5(6H)-one.
 15. A method according to claim 1, wherein Formula A is2-(2-Fluoro-5-methoxyphenyl)imidazo[1,2-c]pyrido[3,4-e]pyrimidin-5(6H)-one.
 16. A method according to claim 1, wherein Formula A is2-(2-Fluoro-4-ethoxyphenyl)imidazo[1,2-c]pyrido[3,4-e]pyrimidin-5(6H)-one.
 17. 2-(4-Ethoxyphenyl)imidazo[1,2-c]pyrido[3,4-e]pyrimidin-5(6H)-one.
 18. A method according to claim 1, wherein Formula A is2-(4-Methylyphenyl)imidazo[1,2-c]pyrido[3,4-e]pyrimidin-5 (6H)-one. 19.A method according to claim 1, wherein Formula A is2-(4-Chlorophenyl)imidazo[1,2-c]pyrido[3,4-e]pyrimidin-5 (6H)-one.
 20. Amethod according to claim 1, wherein Formula A is2-(3-Chlorophenyl)imidazo[1,2-c]pyrido[3,4-e]pyrimidin-5 (6H)-one.
 21. Amethod according to claim 1, wherein Formula A is2phenyl-imidazo[1,2-c]pyrido[3,4-e]pyrimidin-5 (6H)-one.
 22. A methodaccording to claim 1, wherein Formula A is2-(2-Fluorophenyl)imidazo[1,2-c]pyrido[3,4-e]pyrimidin-5 (6H)-one.
 23. Amethod according to claim 1, wherein Formula A is2-(3-Fluorophenyl)imidazo[1,2-c]pyrido[3,4-e]pyrimidin-5 (6H)-one.
 24. Amethod according to claim 1, wherein Formula A is2-(4-Fluorophenyl)imidazo[1,2-c]pyrido[3,4-e]pyrimidin-5 (6H)-one.
 25. Amethod according to claim 1, wherein Formula A is2-(3-Methoxyphenyl)imidazo[1,2-c]pyrido[3,4-e]pyrimidin-5 (6H)-one. 26.A method according to claim 1, wherein Formula A is2-(4-Methoxyphenyl)imidazo[1,2-c]pyrido[3,4-e]pyrimidin-5 (6H)-one. 27.A method according to claim 1, wherein Formula A is2-(2-Fluoro-3-methoxyphenyl)imidazo[1,2-c]pyrido[3,4-e]pyrimidin-5(6H)-one.
 28. A method according to claim 1, wherein Formula A is2-(2-Fluoro-4-methoxyphenyl)imidazo[1,2-c]pyrido[3,4-e]pyrimidin-5(6H)-one.
 29. A method according to claim 1, wherein Formula A is2-(2-Fluoro-5-methoxyphenyl)imidazo[1,2-c]pyrido[3,4-e]pyrimidin-5(6H)-one.
 30. A method according to claim 1, wherein Formula A is2-(2-Fluoro-4-methoxyphenyl)imidazo[1,2-c]pyrido[3,4-e]pyrimidin-5(6H)-one.
 31. A method according to claim 1, wherein Formula A is2-(4-Ethoxyphenyl)imidazo[1,2-c]pyrido[3,4-e]pyrimidin-5 (6H)-one.
 32. Amethod according to claim 1, wherein Formula A is2-(4-Methylphenyl)imidazo[1,2-c]pyrido[3,4-e]pyrimidin-5 (6H)-one.
 33. Amethod according to claim 1, wherein Formula A is2-(4-Chlorophenyl)imidazo[1,2-c]pyrido[3,4-e]pyrimidin-5 (6H)-one.
 34. Amethod according to claim 1, wherein Formula A is2-(3-Chlorophenyl)imidazo[1,2-c]pyrido[3,4-e]pyrimidin-5 (6H)-one.
 35. Amethod according to claim 1, wherein Formula A is7,8-Dimethyl-2-(4-methoxyphenyl)-imidazo [1,2-c]imidazo[4,5-e]pyrimidin-5(6H)-one.
 36. A method according to claim 1, whereinFormula A is 2-(4-Methoxyphenyl)imidazo[1,2-c]thieno[3,4-e]pyrimidin-5(6H)-one.
 37. A method according to claim 1, wherein Formula A is2-(2-Fluoro-4-methoxyphenyl)imidazo[1,2-c]thieno[3,4-e]pyrimidin-5(6H)-one.
 38. A method according to claim 1, wherein Formula A is2-(4-Methoxyphenyl)imidazo[1,2-c]thieno[3,4-e]pyrimidin-5 (6H)-one. 39.A method according to claim 1, wherein Formula A is2-(2-Fluoro-4-methoxyphenyl)imidazo[1,2-c]thieno[3,4-e]pyrimidin-5(6H)-one.
 40. A method according to claim 1, wherein Formula A is2-(4-Methoxyphenyl)imidazo[1,2-c]thieno[3,4-e]pyrimidin-5 (6H)-one. 41.A method according to claim 1, wherein Formula A is2-(2-Fluoro-4-methoxyphenyl)imidazo[1,2-c]thieno[3,4-e]pyrimidin-5(6H)-one.
 42. A method according to claim 1, wherein Formula A is2-(2-Fluoro-4-methoxyphenyl)imidazo[1,2-c]oxazolo[3,4-e]pyrimidin-5(6H)-one.
 43. A method according to claim 1, wherein Formula A is2-(2-Fluoro-4-methoxyphenyl)imidazo[1,2-c]thiazolo[3,4-e]pyrimidin-5(6H)-one.
 44. A method according to claim 1, wherein Formula A is2-(2-Fluoro-4-methoxyphenyl)-7-methyl-imidazo[1,2-c]pyrazolo[3,4-e]pyrimidin-5(6H)-one.